{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:35:07Z","timestamp":1790760907887,"version":"4.1.0"},"reference-count":61,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T00:00:00Z","timestamp":1605571200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T00:00:00Z","timestamp":1605571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["21168"],"award-info":[{"award-number":["21168"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005010","name":"Associazione Italiana per la Ricerca sul Cancro","doi-asserted-by":"publisher","award":["IG-23091"],"award-info":[{"award-number":["IG-23091"]}],"id":[{"id":"10.13039\/501100005010","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Understanding the molecular events controlling melanoma progression is of paramount importance for the development of alternative treatment options for this devastating disease. Here we report a mechanism regulated by the oncogenic SOX2-GLI1 transcriptional complex driving melanoma invasion through the induction of the sialyltransferase ST3GAL1. Using in vitro and in vivo studies, we demonstrate that ST3GAL1 drives melanoma metastasis. Silencing of this enzyme suppresses melanoma invasion and significantly reduces the ability of aggressive melanoma cells to enter the blood stream, colonize distal organs, seed and survive in the metastatic environment. Analysis of glycosylated proteins reveals that the receptor tyrosine kinase AXL is a major effector of ST3GAL1 pro-invasive function. ST3GAL1 induces AXL dimerization and activation that, in turn, promotes melanoma invasion. Our data support a key role of the ST3GAL1-AXL axis as driver of melanoma metastasis, and highlight\u00a0the therapeutic potential of targeting this axis to treat metastatic melanoma.<\/jats:p>","DOI":"10.1038\/s41467-020-19575-2","type":"journal-article","created":{"date-parts":[[2020,11,17]],"date-time":"2020-11-17T11:02:56Z","timestamp":1605610976000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":89,"title":["ST3GAL1 is a target of the SOX2-GLI1 transcriptional complex and promotes melanoma metastasis through AXL"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5544-7286","authenticated-orcid":false,"given":"Silvia","family":"Pietrobono","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Anichini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2219-098X","authenticated-orcid":false,"given":"Cesare","family":"Sala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Manetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana L.","family":"Almada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Pepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan M.","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brooke D.","family":"Paradise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7489-4885","authenticated-orcid":false,"given":"Jann N.","family":"Sarkaria","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8163-6267","authenticated-orcid":false,"given":"Jaime I.","family":"Davila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Tofani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria","family":"Battisti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4103-2733","authenticated-orcid":false,"given":"Giorgio","family":"Arrigoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Ying","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5957-5472","authenticated-orcid":false,"given":"Hu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7462-8288","authenticated-orcid":false,"given":"Alexander","family":"Meves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin E.","family":"Fernandez-Zapico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1197-1622","authenticated-orcid":false,"given":"Barbara","family":"Stecca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,17]]},"reference":[{"key":"19575_CR1","doi-asserted-by":"publisher","first-page":"1056","DOI":"10.1016\/j.ctrv.2014.06.012","volume":"40","author":"D McDermott","year":"2014","unstructured":"McDermott, D. et al. Durable benefit and the potential for long-term survival with immunotherapy in advanced melanoma. Cancer Treat. Rev. 40, 1056\u20131064 (2014).","journal-title":"Cancer Treat. Rev."},{"key":"19575_CR2","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1038\/nm.2616","volume":"18","author":"EL Bird-Lieberman","year":"2012","unstructured":"Bird-Lieberman, E. L. et al. Molecular imaging using fluorescent lectins permits rapid endoscopic identification of dysplasia in Barrett\u2019s esophagus. Nat. Med. 18, 315\u2013321 (2012).","journal-title":"Nat. Med."},{"key":"19575_CR3","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1007\/s10555-012-9359-7","volume":"31","author":"MJ Schultz","year":"2012","unstructured":"Schultz, M. J., Swindall, A. F. & Bellis, S. L. Regulation of the metastatic cell phenotype by sialylated glycans. Cancer Metastasis Rev. 31, 501\u2013518 (2012).","journal-title":"Cancer Metastasis Rev."},{"key":"19575_CR4","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1002\/pmic.201300387","volume":"14","author":"MN Christiansen","year":"2014","unstructured":"Christiansen, M. N. et al. Cell surface protein glycosylation in cancer. Proteomics 14, 525\u2013546 (2014).","journal-title":"Proteomics"},{"key":"19575_CR5","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1038\/nrc3982","volume":"15","author":"SS Pinho","year":"2015","unstructured":"Pinho, S. S. & Reis, C. A. Glycosylation in cancer: mechanisms and clinical implications. Nat. Rev. Cancer 15, 540\u2013555 (2015).","journal-title":"Nat. Rev. Cancer"},{"key":"19575_CR6","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/s10719-016-9755-2","volume":"34","author":"BN Vajaria","year":"2017","unstructured":"Vajaria, B. N. & Patel, P. S. Glycosylation: a hallmark of cancer? Glycoconj. J. 34, 147\u2013156 (2017).","journal-title":"Glycoconj. J."},{"key":"19575_CR7","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.ccell.2019.06.006","volume":"36","author":"S Mereiter","year":"2019","unstructured":"Mereiter, S., Balma\u00f1a, M., Campos, D., Gomes, J. & Reis, C. A. Glycosylation in the era of cancer-targeted therapy: where are we heading? Cancer Cell 36, 6\u201316 (2019).","journal-title":"Cancer Cell"},{"key":"19575_CR8","doi-asserted-by":"publisher","first-page":"3199","DOI":"10.1158\/0008-5472.CAN-14-0728","volume":"74","author":"C B\u00fcll","year":"2014","unstructured":"B\u00fcll, C., Stoel, M. A., den Brok, M. H. & Adema, G. J. Sialic acids sweeten a tumor\u2019s life. Cancer Res. 74, 3199\u20133204 (2014).","journal-title":"Cancer Res."},{"key":"19575_CR9","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.ccr.2011.05.027","volume":"20","author":"A Gaziel-Sovran","year":"2011","unstructured":"Gaziel-Sovran, A. et al. miR-30b\/30d regulation of GalNAc transferases enhances invasion and immunosuppression during metastasis. Cancer Cell 20, 104\u2013118 (2011).","journal-title":"Cancer Cell"},{"key":"19575_CR10","doi-asserted-by":"publisher","first-page":"804","DOI":"10.1016\/j.ccell.2017.05.007","volume":"31","author":"P Agrawal","year":"2017","unstructured":"Agrawal, P. et al. A systems biology approach identifies FUT8 as a driver of melanoma metastasis. Cancer Cell 31, 804\u2013819 (2017).","journal-title":"Cancer Cell"},{"key":"19575_CR11","doi-asserted-by":"publisher","first-page":"4697","DOI":"10.1038\/onc.2014.71","volume":"33","author":"R Santini","year":"2014","unstructured":"Santini, R. et al. SOX2 regulates self-renewal and tumorigenicity of human melanoma-initiating cells. Oncogene 33, 4697\u20134608 (2014).","journal-title":"Oncogene"},{"key":"19575_CR12","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1016\/j.neo.2015.07.001","volume":"17","author":"N Bora-Singhal","year":"2015","unstructured":"Bora-Singhal, N., Perumal, D., Nguyen, J. & Chellappan, S. Gli1-mediated regulation of Sox2 facilitates self-renewal of stem-like cells and confers resistance to EGFR inhibitors in non-small cell lung cancer. Neoplasia 17, 538\u2013551 (2015).","journal-title":"Neoplasia"},{"key":"19575_CR13","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1016\/j.bbadis.2016.11.001","volume":"1863","author":"S Kar","year":"2017","unstructured":"Kar, S., Sengupta, D., Deb, M., Pradhan, N. & Patra, S. K. SOX2 function and Hedgehog signaling pathway are co-conspirators in promoting androgen independent prostate cancer. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 253\u2013265 (2017).","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"19575_CR14","doi-asserted-by":"publisher","first-page":"1808","DOI":"10.1002\/stem.1160","volume":"30","author":"R Santini","year":"2012","unstructured":"Santini, R. et al. Hedgehog-GLI signaling drives self-renewal and tumorigenicity of human melanoma-initiating cells. Stem Cells 30, 1808\u20131818 (2012).","journal-title":"Stem Cells"},{"key":"19575_CR15","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1007\/s00262-005-0019-4","volume":"55","author":"P Laidler","year":"2006","unstructured":"Laidler, P. et al. Characterization of glycosylation and adherent properties of melanoma cell lines. Cancer Immunol. Immunother. 55, 112\u2013118 (2006).","journal-title":"Cancer Immunol. Immunother."},{"key":"19575_CR16","first-page":"djv326","volume":"108","author":"YK Chong","year":"2015","unstructured":"Chong, Y. K. et al. ST3GAL1-associated transcriptomic program in glioblastoma tumor growth, invasion, and prognosis. J. Natl Cancer Inst. 108, djv326 (2015).","journal-title":"J. Natl Cancer Inst."},{"key":"19575_CR17","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-1101-0","volume":"9","author":"X Wu","year":"2018","unstructured":"Wu, X. et al. Sialyltransferase ST3GAL1 promotes cell migration, invasion, and TGF-\u03b21-induced EMT and confers paclitaxel resistance in ovarian cancer. Cell Death Dis. 9, 1102 (2018).","journal-title":"Cell Death Dis."},{"key":"19575_CR18","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8794-1-13","volume":"1","author":"AI Riker","year":"2008","unstructured":"Riker, A. I. et al. The gene expression profiles of primary and metastatic melanoma yields a transition point of tumor progression and metastasis. BMC Med. Genomics 1, 13 (2008).","journal-title":"BMC Med. Genomics"},{"key":"19575_CR19","doi-asserted-by":"publisher","first-page":"e10770","DOI":"10.1371\/journal.pone.0010770","volume":"5","author":"O Kabbarah","year":"2010","unstructured":"Kabbarah, O. et al. Integrative genome comparison of primary and metastatic melanomas. PLoS ONE 5, e10770 (2010).","journal-title":"PLoS ONE"},{"key":"19575_CR20","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1007\/s00109-017-1590-9","volume":"95","author":"E Andreucci","year":"2017","unstructured":"Andreucci, E. et al. Carbonic anhydrase IX inhibition affects viability of cancer cells adapted to extracellular acidosis. J. Mol. Med. 95, 1341\u20131353 (2017).","journal-title":"J. Mol. Med."},{"key":"19575_CR21","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-12-11","volume":"12","author":"X Fang","year":"2011","unstructured":"Fang, X. et al. The SOX2 response program in glioblastoma multiforme: an integrated ChIP-seq, expression microarray, and microRNA analysis. BMC Genomics 12, 11 (2011).","journal-title":"BMC Genomics"},{"key":"19575_CR22","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1242\/dev.124.7.1313","volume":"124","author":"H Sasaki","year":"1997","unstructured":"Sasaki, H., Hui, C., Nakafuku, M. & Kondoh, H. A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124, 1313\u20131322 (1997).","journal-title":"Development"},{"key":"19575_CR23","doi-asserted-by":"publisher","first-page":"2006","DOI":"10.1038\/cdd.2015.56","volume":"22","author":"S Pandolfi","year":"2015","unstructured":"Pandolfi, S., Montagnani, V., Lapucci, A. & Stecca, B. HEDGEHOG\/GLI-E2F1 axis modulates iASPP expression and function and regulates melanoma cell growth. Cell Death Differ. 22, 2006\u20132019 (2015).","journal-title":"Cell Death Differ."},{"key":"19575_CR24","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/jcp.22068","volume":"223","author":"CH Chiang","year":"2010","unstructured":"Chiang, C. H. et al. A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin-mediated signaling. J. Cell Physiol. 223, 492\u2013499 (2010).","journal-title":"J. Cell Physiol."},{"key":"19575_CR25","doi-asserted-by":"publisher","first-page":"E103","DOI":"10.3390\/cancers8110103","volume":"8","author":"EB Rankin","year":"2016","unstructured":"Rankin, E. B. & Giaccia, A. J. The receptor tyrosine kinase AXL in cancer progression. Cancers 8, E103 (2016).","journal-title":"Cancers"},{"key":"19575_CR26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-01573-6","volume":"8","author":"G Restivo","year":"2017","unstructured":"Restivo, G. et al. Low neurotrophin receptor CD271 regulates phenotype switching in melanoma. Nat. Commun. 8, 1988 (2017).","journal-title":"Nat. Commun."},{"key":"19575_CR27","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1146\/annurev-biochem-060614-034402","volume":"84","author":"E Kovacs","year":"2015","unstructured":"Kovacs, E., Zorn, J. A., Huang, Y., Barros, T. & Kuriyan, J. A structural perspective on the regulation of the epidermal growth factor receptor. Annu. Rev. Biochem. 84, 739\u2013764 (2015).","journal-title":"Annu. Rev. Biochem."},{"key":"19575_CR28","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1111\/j.1600-0560.2011.01673.x","volume":"38","author":"B Boone","year":"2011","unstructured":"Boone, B. et al. EGFR in melanoma: clinical significance and potential therapeutic target. J. Cutan. Pathol. 38, 492\u2013502 (2011).","journal-title":"J. Cutan. Pathol."},{"key":"19575_CR29","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/S0065-230X(08)00002-X","volume":"100","author":"RM Linger","year":"2008","unstructured":"Linger, R. M., Keating, A. K., Earp, H. S. & Graham, D. K. TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Adv. Cancer Res. 100, 35\u201383 (2008).","journal-title":"Adv. Cancer Res."},{"key":"19575_CR30","doi-asserted-by":"publisher","first-page":"2448","DOI":"10.1038\/jid.2011.218","volume":"131","author":"M Sensi","year":"2011","unstructured":"Sensi, M. et al. Human cutaneous melanomas lacking MITF and melanocyte differentiation antigens express a functional Axl receptor kinase. J. Invest. Dermatol. 131, 2448\u20132457 (2011).","journal-title":"J. Invest. Dermatol."},{"key":"19575_CR31","doi-asserted-by":"publisher","first-page":"2634","DOI":"10.1158\/0008-5472.CAN-18-2316","volume":"79","author":"OY Revach","year":"2019","unstructured":"Revach, O. Y., Sandler, O., Samuels, Y. & Geiger, B. Cross-talk between receptor tyrosine kinases AXL and ERBB3 regulates invadopodia formation in melanoma cells. Cancer Res. 79, 2634\u20132648 (2019).","journal-title":"Cancer Res."},{"key":"19575_CR32","doi-asserted-by":"publisher","first-page":"3275","DOI":"10.1038\/s41388-018-0205-4","volume":"37","author":"Q Zuo","year":"2018","unstructured":"Zuo, Q. et al. AXL\/AKT axis mediated-resistance to BRAF inhibitor depends on PTEN status in melanoma. Oncogene 37, 3275\u20133289 (2018).","journal-title":"Oncogene"},{"key":"19575_CR33","first-page":"1365","volume":"25","author":"H Cui","year":"2011","unstructured":"Cui, H., Lin, Y., Yue, L., Zhao, X. & Liu, J. Differential expression of the e to BRAF i acid residues in breast cancer is associated with metastatic potential. Oncol. Rep. 25, 1365\u20131371 (2011).","journal-title":"Oncol. Rep."},{"key":"19575_CR34","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1093\/glycob\/cwq085","volume":"20","author":"G Picco","year":"2010","unstructured":"Picco, G. et al. Over-expression of ST3Gal-I promotes mammary tumorigenesis. Glycobiology 20, 1241\u20131250 (2010).","journal-title":"Glycobiology"},{"key":"19575_CR35","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1038\/labinvest.2011.188","volume":"92","author":"SD Girouard","year":"2012","unstructured":"Girouard, S. D. et al. SOX2 contributes to melanoma cell invasion. Lab Invest. 92, 362\u2013370 (2012).","journal-title":"Lab Invest."},{"key":"19575_CR36","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1111\/j.1600-0625.2011.01247.x","volume":"20","author":"AC Laga","year":"2011","unstructured":"Laga, A. C. et al. SOX2 and nestin expression in human melanoma: an immunohistochemical and experimental study. Exp. Dermatol. 20, 339\u2013345 (2011).","journal-title":"Exp. Dermatol."},{"key":"19575_CR37","doi-asserted-by":"publisher","first-page":"6561","DOI":"10.1158\/0008-5472.CAN-18-0330","volume":"78","author":"D Ravindran Menon","year":"2018","unstructured":"Ravindran Menon, D. et al. CDK1 interacts with Sox2 and promotes tumor initiation in human melanoma. Cancer Res. 78, 6561\u20136574 (2018).","journal-title":"Cancer Res."},{"key":"19575_CR38","doi-asserted-by":"publisher","first-page":"424","DOI":"10.7150\/thno.29698","volume":"9","author":"Q Jia","year":"2019","unstructured":"Jia, Q. et al. Low levels of Sox2 are required for melanoma tumor-repopulating cell dormancy. Theranostics 9, 424\u2013435 (2019).","journal-title":"Theranostics"},{"key":"19575_CR39","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-018-0297-z","volume":"16","author":"E Andreucci","year":"2018","unstructured":"Andreucci, E. et al. SOX2 as a novel contributor of oxidative metabolism in melanoma cells. Cell Commun. Signal. 16, 87 (2018).","journal-title":"Cell Commun. Signal."},{"key":"19575_CR40","doi-asserted-by":"publisher","first-page":"5895","DOI":"10.1073\/pnas.0700776104","volume":"104","author":"B Stecca","year":"2007","unstructured":"Stecca, B. et al. Melanomas require Hedgehog-Gli signaling regulated by interactions between Gli1 and the RAS-MEK\/AKT pathways. Proc. Natl Acad. Sci. USA 104, 5895\u20135900 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"19575_CR41","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1093\/jnci\/djq257","volume":"102","author":"VI Alexaki","year":"2010","unstructured":"Alexaki, V. I. et al. GLI2-mediated melanoma invasion and metastasis. J. Natl Cancer Inst. 102, 1148\u20131159 (2010).","journal-title":"J. Natl Cancer Inst."},{"key":"19575_CR42","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1111\/cas.13294","volume":"108","author":"IK Gunarta","year":"2017","unstructured":"Gunarta, I. K. et al. Critical role of glioma-associated oncogene homolog 1 in maintaining invasive and mesenchymal-like properties of melanoma cells. Cancer Sci. 108, 1602\u20131611 (2017).","journal-title":"Cancer Sci."},{"key":"19575_CR43","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1090-3","volume":"18","author":"C Zhu","year":"2019","unstructured":"Zhu, C., Wei, Y. & Wei, X. AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol. Cancer 18, 153 (2019).","journal-title":"Mol. Cancer"},{"key":"19575_CR44","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/sj.emboj.7600912","volume":"25","author":"T Sasaki","year":"2006","unstructured":"Sasaki, T. et al. Structural basis for Gas6-Axl signalling. EMBO J. 25, 80\u201387 (2006).","journal-title":"EMBO J."},{"key":"19575_CR45","doi-asserted-by":"publisher","first-page":"8818","DOI":"10.18632\/oncotarget.2422","volume":"5","author":"H Axelrod","year":"2014","unstructured":"Axelrod, H. & Pienta, K. J. Axl as a mediator of cellular growth and survival. Oncotarget 5, 8818\u20138852 (2014).","journal-title":"Oncotarget"},{"key":"19575_CR46","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1038\/nm.4472","volume":"24","author":"J Boshuizen","year":"2018","unstructured":"Boshuizen, J. et al. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF\/MEK inhibitors. Nat. Med. 24, 203\u2013212 (2018).","journal-title":"Nat. Med."},{"key":"19575_CR47","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1038\/s41568-019-0154-4","volume":"19","author":"I Arozarena","year":"2019","unstructured":"Arozarena, I. & Wellbrock, C. Phenotype plasticity as enabler of melanoma progression and therapy resistance. Nat. Rev. Cancer 19, 377\u2013391 (2019).","journal-title":"Nat. Rev. Cancer"},{"key":"19575_CR48","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1158\/2159-8290.CD-13-0424","volume":"4","author":"DJ Konieczkowski","year":"2014","unstructured":"Konieczkowski, D. J. et al. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov. 4, 816\u2013827 (2014).","journal-title":"Cancer Discov."},{"key":"19575_CR49","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1093\/jmcb\/mjw045","volume":"9","author":"A De Polo","year":"2017","unstructured":"De Polo, A. et al. AXL receptor signalling suppresses p53 in melanoma through stabilization of the MDMX-MDM2 complex. J. Mol. Cell Biol. 9, 154\u2013165 (2017).","journal-title":"J. Mol. Cell Biol."},{"key":"19575_CR50","doi-asserted-by":"publisher","first-page":"138","DOI":"10.3389\/fonc.2015.00138","volume":"5","author":"A Vasconcelos-Dos-Santos","year":"2015","unstructured":"Vasconcelos-Dos-Santos, A. et al. Biosynthetic machinery involved in aberrant glycosylation: promising targets for developing of drugs against cancer. Front. Oncol. 5, 138 (2015).","journal-title":"Front. Oncol."},{"key":"19575_CR51","doi-asserted-by":"publisher","first-page":"3322","DOI":"10.1038\/onc.2016.481","volume":"36","author":"M Riverso","year":"2017","unstructured":"Riverso, M., Montagnani, V. & Stecca, B. KLF4 is regulated by RAS\/RAF\/MEK\/ERK signaling through E2F1 and promotes melanoma cell growth. Oncogene 36, 3322\u20133333 (2017).","journal-title":"Oncogene"},{"key":"19575_CR52","doi-asserted-by":"publisher","first-page":"2059","DOI":"10.1016\/j.jid.2016.06.610","volume":"136","author":"S Pietrobono","year":"2016","unstructured":"Pietrobono, S. et al. Down-regulation of SOX2 underlies the inhibitory effects of the triphenylmethane gentian violet on melanoma cell self-renewal and survival. J. Invest. Dermatol. 136, 2059\u20132069 (2016).","journal-title":"J. Invest. Dermatol."},{"key":"19575_CR53","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1038\/s41586-019-0969-x","volume":"566","author":"J Cao","year":"2019","unstructured":"Cao, J. et al. The single-cell transcriptional landscape of mammalian organogenesis. Nature 566, 496\u2013502 (2019).","journal-title":"Nature"},{"key":"19575_CR54","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/s41586-019-1847-2","volume":"577","author":"A Tasdogan","year":"2020","unstructured":"Tasdogan, A. et al. Metabolic heterogeneity confers differences in melanoma metastatic potential. Nature 577, 115\u2013120 (2020).","journal-title":"Nature"},{"key":"19575_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-017-0142-0","volume":"9","author":"S Pietrobono","year":"2018","unstructured":"Pietrobono, S. et al. Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe. Cell Death Dis. 9, 142 (2018).","journal-title":"Cell Death Dis."},{"key":"19575_CR56","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/978-1-4939-1789-1_3","volume":"1233","author":"HF Turk","year":"2015","unstructured":"Turk, H. F. & Chapkin, R. S. Analysis of epidermal growth factor receptor dimerization by BS\u00b3 cross-linking. Methods Mol. Biol. 1233, 25\u201334 (2015).","journal-title":"Methods Mol. Biol."},{"key":"19575_CR57","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/nmeth.1322","volume":"6","author":"JR Wi\u015bniewski","year":"2009","unstructured":"Wi\u015bniewski, J. R., Zougman, A., Nagaraj, N. & Mann, M. Universal sample preparation method for proteome analysis. Nat. Methods 6, 359\u2013362 (2009).","journal-title":"Nat. Methods"},{"key":"19575_CR58","doi-asserted-by":"publisher","first-page":"1367","DOI":"10.1038\/nbt.1511","volume":"26","author":"J Cox","year":"2008","unstructured":"Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367\u20131372 (2008).","journal-title":"Nat. Biotechnol."},{"key":"19575_CR59","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1021\/pr101065j","volume":"10","author":"J Cox","year":"2011","unstructured":"Cox, J. et al. Andromeda: a peptide search engine integrated into the MaxQuant environment. J. Proteome Res. 10, 1794\u20131805 (2011).","journal-title":"J. Proteome Res."},{"key":"19575_CR60","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","volume":"2","author":"E Cerami","year":"2012","unstructured":"Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401\u2013404 (2012).","journal-title":"Cancer Discov."},{"key":"19575_CR61","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1126\/scisignal.2004088","volume":"6","author":"J Gao","year":"2013","unstructured":"Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, 11 (2013).","journal-title":"Sci. Signal."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-020-19575-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-020-19575-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-020-19575-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,12]],"date-time":"2023-10-12T14:03:53Z","timestamp":1697119433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-020-19575-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,17]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["19575"],"URL":"https:\/\/doi.org\/10.1038\/s41467-020-19575-2","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,17]]},"assertion":[{"value":"23 October 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5865"}}